Fatty acid amide hydrolase inhibitors: A patent review (2009 - 2014)

Expert Opinion on Therapeutic Patents

Volumn 25, Issue 11, 2015, Pages 1247-1266

  Lodola, Alessio ^a   Castelli, Riccardo ^a   Mor, Marco ^a   Rivara, Silvia ^a  

^a UNIVERSITY OF PARMA   (Italy)

Author keywords

endocannabinoid system; fatty acid amide hydrolase; fatty acid ethanolamides; PF 04457845; URB597

Indexed keywords

ALPHA KETOHETEROCYCLE DERIVATIVE; ANANDAMIDE; BORONIC ACID DERIVATIVE; CARBAMIC ACID; CARBAMIC ACID INHIBITOR; ETHYLAMINOPYRIMIDINE DERIVATIVE; FATTY ACID AMIDASE INHIBITOR; N (3 PYRIDAZINYL) 4 [3 (5 TRIFLUOROMETHYL 2 PYRIDINYLOXY)BENZYLIDENE] 1 PIPERIDINECARBOXAMIDE; PYRROLE DERIVATIVE; TETRAHYDRONAPHTHYRIDINE DERIVATIVE; UNCLASSIFIED DRUG; UREA DERIVATIVE; AMIDASE; AMIDE; ARACHIDONIC ACID DERIVATIVE; ENDOCANNABINOID; ENZYME INHIBITOR; FATTY-ACID AMIDE HYDROLASE;

DRUG POTENCY; DRUG SELECTIVITY; DRUG TREATMENT FAILURE; ENZYME ACTIVITY; ENZYME STRUCTURE; HUMAN; INFLAMMATION; MOOD DISORDER; NONHUMAN; OSTEOARTHRITIS; PAIN; PATENT; PHASE 2 CLINICAL TRIAL (TOPIC); REVIEW; ANIMAL; ANTAGONISTS AND INHIBITORS; CENTRAL NERVOUS SYSTEM DISEASES; DRUG DESIGN; ENZYMOLOGY; METABOLISM;

AMIDOHYDROLASES; ANIMALS; ARACHIDONIC ACIDS; CENTRAL NERVOUS SYSTEM DISEASES; DRUG DESIGN; ENDOCANNABINOIDS; ENZYME INHIBITORS; HUMANS; INFLAMMATION; PAIN; PATENTS AS TOPIC; POLYUNSATURATED ALKAMIDES;

EID: 84946550619     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2015.1067683     Document Type: Review

References (123)

1. Piomelli D. The molecular logic of endocannabinoid signaling. Nat Rev Neurosci 2003;4:873-84
2. Pertwee RG, Ross RA. Cannabinoid receptors and their ligands. Prostaglandins Leukot Essent Fatty Acids 2002;66:101-21
3. Sugiura T, Waku K. 2-Arachidonoylglycerol and the cannabinoid receptors. Chem Phys Lipids 2000;108:89-106
4. Cravatt BF, Lichtman AH. The enzymatic inactivation of the fatty acid amide class of signaling lipids. Chem Phys Lipids 2002;121:135-48
5. Lambert DM, Vandevoorde S, Jonsson K-O, et al. The palmitoylethanolamide family: A new class of anti-inflammatory agents? Curr Med Chem 2002;9:663-74
6. Solorzano C, Zhu C, Battista N, et al. Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation. Proc Natl Acad Sci 2009;106:20966-71
7. Fu J, Gaetani S, Oveisi F, et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 2003;425:90-3
8. Muccioli GG. Endocannabinoid biosynthesis and inactivation, from simple to complex. Drug Discov Today 2010;15:474-83
9. Ahn K, Mckinney MK, Cravatt BF. Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem Rev 2008;108:1687-707
10. Alger BE, Kim J. Supply and demand for endocannabinoids. Trends Neurosci 2011;34:304-15
11. Ueda N, Tsuboi K, Uyama T. Enzymological studies on the biosynthesis of N-acylethanolamines. Biochim Biophys Acta 2010;1801:1274-85
12. Magotti P, Bauer I, Igarashi M, et al. Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids. Structure 2015;23:598-604
13. Fu J, Bottegoni G, Sasso O, et al. A catalytically silent FAAH-1 variant drives anandamide transport in neurons. Nat Neurosci 2012;15:64-9
14. Kaczocha M, Vivieca S, Sun J, et al. Fatty acid-binding proteins transport N-acylethanolamines to nuclear receptors and are targets of endocannabinoid transport inhibitors. J Biol Chem 2012;287:3415-24
15. Ligresti A, Morera E, Van Der Stelt M, et al. Further evidence for the existence of a specific process for the membrane transport of anandamide. Biochem J 2004;380:265-72
16. Cravatt BF, Lichtman AH. Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr Opin Chem Biol 2003;7:469-75
17. Labar G, Michaux C. Fatty acid amide hydrolase: from characterization to therapeutics. Chem Biodivers 2007;4:1882-902
18. Cravatt BF, Giang DK, Mayfield SP, et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 1996;84:83-7
19. Di Marzo V, Fontana A, Cadas H, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 1994;372:686-91
20. Ueda N, Tsuboi K, Uyama T. N-acylethanolamine metabolism with special reference to N-acylethanolaminehydrolyzing acid amidase (NAAA). Prog Lipid Res 2010;49:299-315
21. Tsuboi K, Sun Y-X, Okamoto Y, et al. Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase. J Biol Chem 2005;280:11082-92
22. Blankman JL, Cravatt BF. Chemical probes of endocannabinoid metabolism. Pharmacol Rev 2013;65:849-71
23. Cravatt BF, Demarest K, Patricelli MP, et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 2001;98:9371-6
24. Kathuria S, Gaetani S, Fegley D, et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 2003;9:76-81
25. Justinova Z, Mangieri RA, Bortolato M, et al. Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates. Biol Psychiatry 2008;64:930-7
26. Justinova Z, Panlilio LV, Moreno-Sanz G, et al. Effects of fatty acid amide hydrolase (FAAH) inhibitors in non-human primate models of nicotine reward and relapse. Neuropsychopharmacology 2015. [Epub ahead of print]
27. Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov 2008;7:438-55
28. McKinney MK, Cravatt BF. Structure and function of fatty acid amide hydrolase. Annu Rev Biochem 2005;74:411-32
29. Lodola A, Mor M, Sirirak J, et al. Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/MM) modelling. Biochem Soc Trans 2009;37:363-7
30. Bracey MH, Hanson MA, Masuda KR, et al. Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science 2002;298:1793-6
31. Bertolacci L, Romeo E, Veronesi M, et al. A binding site for nonsteroidal anti-inflammatory drugs in fatty acid amide hydrolase. J Am Chem Soc 2013;135(1):22-5
32. Seierstad M, Breitenbucher JG. Discovery and development of fatty acid amide hydrolase (FAAH) inhibitors. J Med Chem 2008;51:7327-43
33. Boger DL, Miyauchi H, Du W, et al. Discovery of a potent, selective, and efficacious class of reversible alphaketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics. J Med Chem 2005;48(6):1849-56
34. Mileni M, Garfunkle J, DeMartino JK, et al. Binding and inactivation mechanism of a humanized fatty acid amide hydrolase by a-ketoheterocycle inhibitors revealed from cocrystal structures. J Am Chem Soc 2009;131:10497-506
35. Lichtman AH, Leung D, Shelton CC, et al. Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J Pharmacol Exp Ther 2004;311:441-8
36. The Regents of the University of California. Modulation of anxiety through blockade of anandamide hydrolysis. WO2004033422; 2004
37. Mor M, Rivara S, Lodola A, et al. Cyclohexylcarbamic Acid 3′- or 4′- Substituted Biphenyl-3-yl Esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure-activity relationships, and molecular modeling studies. J Med Chem 2004;47:4998-5008
38. Alexander JP, Cravatt BF. Mechanism of carbamate inactivation of FAAH: implications for the design of covalent inhibitors and in vivo functional probes for enzymes. Chem Biol 2005;12:1179-87
39. Lodola A, Capoferri L, Rivara S, et al. Quantum mechanics/molecular mechanics modeling of fatty acid amide hydrolase reactivation distinguishes substrate from irreversible covalent inhibitors. J Med Chem 2013;56:2500-12
40. Piomelli D, Tarzia G, Duranti A, et al. Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev 2006;12:21-38
41. Sit SY, Conway C, Bertekap R, et al. Novel inhibitors of fatty acid amide hydrolase. Bioorg Med Chem Lett 2007;17:3287-91
42. Otrubova K, Ezzili C, Boger DL. The discovery and development of inhibitors of fatty acid amide hydrolase (FAAH). Bioorg Med Chem Lett 2011;21:4674-85
43. Ahn K, Johnson DS, Fitzgerald LR, et al. Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity. Biochemistry 2007;46:13019-30
44. Palermo G, Branduardi D, Masetti M, et al. Covalent inhibitors of fatty acid amide hydrolase: a rationale for the activity of piperidine and piperazine aryl ureas. J Med Chem 2011;6612-23
45. Ahn K, Johnson DS, Mileni M, et al. Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. Chem Biol 2009;16:411-20
46. Takeda Pharmaceutical Company Limited. Amide compound. WO2006054652; 2006
47. Karbarz MJ, Luo L, Chang L, et al. Biochemical and biological properties of 4-(3-phenyl-[1,2,4]thiadiazol-5-yl)- piperazine-1-carboxylic acid phenylamide, a mechanism-based inhibitor of fatty acid amide hydrolase. Anesth Analg 2009;108:316-29
48. Di Marzo V. Inhibitors of endocannabinoid breakdown for pain: not so FA(AH)cile, after all. Pain 2012;153:1785-6
49. Min X, Thibault ST, Porter AC, et al. Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH). Proc Natl Acad Sci USA 2011;108:7379-84
50. Bisogno T, Maccarrone M. Latest advances in the discovery of fatty acid amide hydrolase inhibitors. Expert Opin Drug Discov 2013;8:509-22
51. Feledziak M, Lambert DM, Marchand-Brynaert J, et al. Inhibitors of the endocannabinoid degrading enzymes, or how to increase endocannabinoid's activity by preventing their hydrolysis. Recent Pat CNS Drug Discov 2012;7:49-70
52. Scripps Research Institute. Alpha-keto heterocycles as FAAH inhibitors. WO2010005572; 2010
53. Boger DL. Alpha-ketoheterocycles and methods of making and using. WO2012106569; 2012
54. Ezzili C, Mileni M, McGlinchey N, et al. Reversible competitive aketoheterocycle inhibitors of fatty acid amide hydrolase containing additional conformational constraints in the acyl side chain: orally active, long-acting analgesics. J Med Chem 2011;54:2805-22
55. Janssen Pharmaceutica N.V. 2-Keto-oxazoles as modulators of fatty acid amide hydrolase. US20090111778; 2009
56. Janssen Pharmaceutica N.V. Oxazolyl piperidine modulators of fatty acid amide hydrolase. US20100292266; 2010
57. Vacondio F, Silva C, Lodola A, et al. Structure-property relationships of a class of carbamate-based fatty acid amide hydrolase (FAAH) inhibitors: chemical and biological stability. Chem Med Chem 2009;4:1495-504
58. Clapper JR, Vacondio F, King AR, et al. A second generation of carbamate-based fatty acid amide hydrolase inhibitors with improved activity in vivo. Chem Med Chem 2009;4:1505-13
59. Clapper JR, Moreno-Sanz G, Russo R, et al. Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat Neurosci 2010;13:1265-70
60. The Regents of the University of California, Università degli Studi di Urbino "Carlo Bo", Università degli Studi di Parma. Peripherally restricted FAAH inhibitors. WO2012015704; 2012
61. Fondazione Istituto Italiano di Tecnologia, the Regents of the University of California; Alma Mater Studiorum-Università di Bologna. Multitarget FAAH and COX inhibitors and therapeutical uses thereof. WO2014023643; 2014
62. Sasso O, Migliore M, Habrant D, et al. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage. FASEB J 2015;29(6):2616-27
63. Sigma-Tau Industrie Farmaceutche Riunite S.p.A. Enol carbamate derivatives as modulators of fatty acid amide hydrolase. WO2009109504; 2009
64. Gattinoni S, De Simone C, Dallavalle S, et al. Enol carbamates as inhibitors of fatty acid amide hydrolase (FAAH) endowed with high selectivity for FAAH over the other targets of the endocannabinoid system. Chem Med Chem 2010;5:357-60
65. Caprioli A, Coccurello R, Rapino C, et al. The novel reversible fatty acid amide hydrolase inhibitor ST4070 increases endocannabinoid brain levels and counteracts neuropathic pain in different animal models. J Pharmacol Exp Ther 2012;342:188-95
66. Sigma Tau Industrie Farmaceutche Riunite S.p.A. Oxime carbamoyl derivatives as modulators of fatty acid amides hydrolase. WO2009138416; 2009
67. Sigma Tau Industrie Farmaceutche Riunite S.p.A. Carbamate derivatives in particular for the treatment of neurological disorders. WO2010105930; 2010
68. Butini S, Brindisi M, Gemma S, et al. Discovery of potent inhibitors of human and mouse fatty acid amide hydrolases. J Med Chem 2012;55:6898-915
69. Sanofi-Aventis. Alkylthiazol carbamate derivatives, preparation thereof and therapeutic use thereof. WO2010010288; 2010
70. Sanofi Aventis. Carbamate derivatives of alkyl-heterocycles, preparation thereof and therapeutic use thereof. WO2010055267; 2010
71. Sanofi Aventis. Carbamate derivatives of alkyl-heterocycles, preparation thereof and therapeutic use thereof. WO2010130945; 2010
72. Astellas Pharma Inc. Azole compound. WO2010007966; 2010
73. Pfizer Inc. Ether benzylidene piperidine aryl carboxamide compounds useful as FAAH inhibitors. WO2009127944; 2009
74. Pfizer Inc. 4-[3-(Aryloxy)benzylidene]-3-methylpiperidine aryl carboxamide compounds useful as FAAH inhibitors. WO2009127949; 2009
75. Pfizer Inc. 7-azaspiro[3.5]nonane-7-carboxamide compounds as modulators of fatty acid amide hydrolase. WO2010049841; 2010
76. Pfizer Inc. Preparation of 1-Oxa-8-azaspiro[4,5]decane-8-carboxamide compounds as FAAH inhibitors. WO2010058318; 2010
77. Meyers MJ, Long SA, Pelc MJ, et al. Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 1: identification of 7-azaspiro[3.5] nonane and 1-oxa-8-azaspiro[4.5]decane as lead scaffolds. Bioorg Med Chem Lett 2011;21(21):6538-44
78. Meyers MJ, Long SA, Pelc MJ, et al. Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5] nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain. Bioorg Med Chem Lett 2011;21(21):6545-53
79. Feledziak M, Lambert DM, Marchand-Brynaert J, et al. Inhibitors of the Endocannabinoid-Degrading Enzymes, or how to Increase Endocannabinoids Activity by Preventing their Hydrolysis. Recent Pat CNS Drug Discov 2012;7(1):49-70
80. Hart T, Macias AT, Benwell K, et al. Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas. Bioorg Med Chem Lett 2009;19(15):4241-4
81. Roughley SD, Browne H, Macias AT, et al. Fatty acid amide hydrolase inhibitors. 3: tetra-substituted azetidine ureas with in vivo activity. Bioorg Med Chem Lett 2012;22(2):901-6
82. Vernalis (R&D) LTD. Azetidine derivatives. WO2009109743; 2009
83. Janssen Pharmaceutica N.V. Heteroaryl-substituted urea modulators of fatty acid amide hydrolase. WO2010068452; 2010
84. Janssen Pharmaceutica N.V. Heteroaryl-substituted urea modulators of fatty acid amide hydrolase. WO2010068453; 2010
85. Janssen Pharmaceutica N.V. Heteroaryl-substituted urea modulators of fatty acid amide hydrolase. US2009062294; 2009
86. Janssen Pharmaceutica N.V. Heteroaryl-substituted spirocyclic diamine urea modulators of fatty acid amide hydrolase. WO2010141817; 2010
87. Keith JM, Jones WM, Pierce JM, et al. Heteroarylureas with spirocyclic diamine cores as inhibitors of fatty acid amide hydrolase. Bioorg Med Chem Lett 2014;24(3):737-41
88. Janssen pharmaceutica N.V. Piperazinecarboxamide derivative useful as a modulator of fatty acid amide hydrolase (FAAH). WO2011060026; 2011
89. Janssen Pharmaceutica N.V. Modulators of fatty acid amide hydrolase. WO2011139951; 2011
90. Janssen Pharmaceutica N.V. Aryl-substituted heterocyclic urea modulators of fatty acid amide hydrolase. WO2010141809; 2010
91. Bial-Portela & C. S.A. Pharmaceutical. WO2010074588; 2010
92. Northeastern University. Inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase for modulation of cannabinoid receptors. WO2009117444; 2009
93. Infinity Discovery, Inc. Inhibitors of fatty acid amide hydrolase. WO2008063300; 2008
94. Minkkila A, Saario SM, Kasnanen H, et al. Discovery of boronic acids as novel and potent inhibitors of fatty acid amide hydrolase. J Med Chem 2008;51(22):7057-60
95. Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase. WO2009126691; 2009
96. Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase. WO2010118155; 2010
97. Infinity Discovery, Inc. Inhibitors of fatty acid amide hydrolase. WO2010118159; 2010
98. Merck & Co., Inc. Imidazole derivatives useful as inhibitors of FAAH. WO2009152025; 2009
99. Merck & Co., Inc. Pyrazole derivatives useful as inhibitors of FAAH. WO2009151991; 2009
100. Merck Sharp & Dohme Corp. Oxazole derivatives useful as modulators of FAAH. WO 2011126960; 2011
101. Merck Sharp & Dohme Corp. Aza-indole derivatives useful as modulators of FAAH. WO2011140164; 2011
102. Merck Sharp & Dohme Corp. Imidazole derivatives useful as modulators of FAAH and as FAAH imaging agents. WO2010101724; 2010
103. Liu P, Hamill TG, Chioda M, et al. Discovery of MK-3168: A PET tracer for imaging brain fatty acid amide hydrolase. ACS Med Chem Lett 2013;4(6):509-13
104. Chobanian HR, Guo Y, Liu P, et al. Discovery of MK-4409, a novel oxazole FAAH inhibitor for the treatment of inflammatory and neuropathic pain. ACS Med Chem Lett 2014;5(6):717-21
105. Janssen Pharmaceutica N.V. Aryl-hydroxyethylamino-pyrimidines and triazines as modulators of fatty acid amide hydrolase. WO2009105220; 2009
106. Keith JM, Hawryluk N, Apodaca RL, et al. 1-Aryl-2-((6-aryl)pyrimidin-4-yl) amino)ethanols as competitive inhibitors of fatty acid amide hydrolase. Bioorg Med Chem Lett 2014;24(5):1280-4
107. Janssen Pharmaceutica N.V. Ethylene diamine modulators of fatty acid amide hydrolase. WO2011022348; 2011
108. Renovis Inc. Compounds useful as FAAH modulators and uses thereof. WO 2009011904; 2009
109. Gowlugari S, De Falco J, Nguyen MT, et al. Discovery of potent, non-carbonyl inhibitors of fatty acid amide hydrolase (FAAH). Med Chem Commun 2012;3:1258-63
110. Renovis. Preparation of benzoxazole compounds as FAAH modulators. WO 2010039186; 2010
111. Bial-Portela & Companhia, S.A. 5-O-Substituted 3-N-phenyl-1,3,4-oxadiazolones for medical use. WO2009084970; 2009
112. Bial-Portela & Companhia, S.A. 5-O-Substituted 3-N-phenyl-1,3,4-oxadiazolones for medical use. WO2010074587; 2010
113. Bial-Portela & Companhia, S.A. 5-O-Substituted 3-N-phenyl-1,3,4-oxadiazolones for medical use. WO2010151160; 2010
114. Ben Ali Y, Chahinian H, Petry S, et al. Use of an inhibitor to identify members of the hormone-sensitive lipase family. Biochemistry 2006;45(47):14183-91
115. Infinity Pharmaceuticals, Inc. Isoxazolines as inhibitors of fatty acid amide hydrolase. WO2010135360; 2010
116. Ironwood Pharmaceuticals, Inc. FAAH inhibitors. WO2011071996; 2011
117. Ironwood Pharmaceuticals, Inc. FAAH inhibitors. WO2012088469; 2012
118. Bachovchin DA, Cravatt BF. The pharmacological landscape and therapeutic potential of serine hydrolases. Nat Rev Drug Discov 2012;11(1):52-68
119. Ironwood Pharmaceuticals, Inc. Use of FAAH inhibitors as neuroprotective agents in the CNS. WO2014004676; 2014
120. Ironwood Pharmaceuticals, Inc. Use of FAAH inhibitors for treating Parkinson's disease and restless legs syndrome. WO2011085216; 2011
121. Banijamali AR, Wakefield JD, Mermerian AH, et al. Metabolism and disposition of MM-433593, a selective FAAH-1 inhibitor, in monkeys. Pharmacol Res Perspect 2014;2(5):e00059
122. Allergan, Inc. Fatty acid amide hydrolase inhibitors for treating. WO2012145737; 2012
123. Forster L, Ludwig J, Kaptur M, et al. 1-Indol-1-yl-propan-2-ones and related heterocyclic compounds as dual inhibitors of cytosolic phospholipase A(2) alpha and fatty acid amide hydrolase. Bioorg Med Chem 2010;18(2):945-52